Malate salt of N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N′(4-fluorophenyl)cyclopropane-1,1-dicarboxamide, and crystalline forms therof for the treatment of cancer

Abstract

Disclosed are malate salts of N-(4-{[6,7-bis(methyloxy)-quinolin-4-yl]oxy}phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide, including a (L)-malate salt, a (D)-malate salt, a (DL) malate salt, and mixtures thereof; and crystalline and amorphous forms of the malate salts. Also disclosed are pharmaceutical compositions comprising at least one malate salts of N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N′-(4-fluorophenyl)-cyclopropane-1,1-dicarboxamide; and methods of treating cancer comprising administering at least one malate salt of N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide.

What is claimed is: 
     
       1. N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N′-(4-fluorophenyl) cyclopropane-1,1-dicarboxamide (L) malate salt, wherein said salt is in crystalline Form N-1 and said Form N-1 is characterized by at least one of the following:
 (i) a solid state  13 C NMR spectrum with four or more peaks selected from 18.1, 42.9, 44.5, 70.4, 123.2, 156.2, 170.8, 175.7, and 182.1, ±0.2 ppm; 
 (ii) a powder x-ray diffraction pattern (CuKα λ=1.5418 Å) comprising four or more 2θ values selected from: 12.8±0.2° 2θ, 13.5±0.2° 2θ, 16.9±0.2° 2θ, 19.4±0.2° 2θ, 21.5±0.2° 2θ, 22.8±0.2° 2θ, 25.1±0.2° 2θ, 27.6±0.2° 2θ, wherein measurement of the crystalline form is at room temperature; and/or 
 (iii) an x-ray powder diffraction (XRPD) pattern substantially in accordance with the pattern shown in  FIG. 1 . 
 
     
     
       2. A pharmaceutical composition comprising the N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N′-(4-fluorophenyl) cyclopropane-1,1-dicarboxamide (L) malate salt according to  claim 1 ; and a pharmaceutically acceptable excipient. 
     
     
       3. A method of treating thyroid cancer in a subject comprising administration of the N-1 form of crystalline N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N-(4-fluorophenyl) cyclopropane-1,1-dicarboxamide (L) malate salt according to  claim 1 . 
     
     
       4. A method of treating glioblastoma in a subject comprising administration of the N-1 form of crystalline N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (L) malate salt according to  claim 1 . 
     
     
       5. The method of  claim 3 , wherein the thyroid cancer is medullary thyroid cancer.